Exploring the role of active site Mn²⁺ ions in the binding of protein phosphatase 5 with its substrate using molecular dynamics simulations.

Protein phosphatase 5 (PP5), an important member of serine/threonine protein phosphatases, has been associated with diverse human cancers. Structural data demonstrate that two metal ions and two water molecules are located in the active site of PP5 and are involved in the dephosphorylations of the substrate. Recently, the catalytic reaction of PP5 has been studied by a density functional theory (DFT) method, and the role of the water molecules in regulating the substrate binding of PP5 was explored by our previous molecular dynamics (MD) study. These two studies enrich our understanding of the catalytic mechanism of PP5. However, the questions of how the metal ions regulate the substrate binding and the contribution of each metal ion to the catalysis remain not answered. To this end, the role of the catalytic Mn²⁺ ions in regulating the binding of PP5 with its substrate was investigated through MD simulations. Results reveal that the different states of Mn²⁺ ions can alter the structure of the active site and the conformations of the residues coordinating the Mn²⁺ ions or the substrate. This leads to changes in the secondary structure and dynamical fluctuation of PP5, especially for that of helix αJ. With the position change of helix αJ, the volume of the substrate binding pocket is altered by the different states of Mn²⁺ ions, indicating the regulatory role of Mn²⁺ ions in PP5 activity. Furthermore, combined with the simulation data of our previous study, the sequential steps for PP5 binding of the substrate, the two active site water molecules, and the two Mn²⁺ ions are proposed. This may help to develop new inhibitors to treat the PP5-related cancers.

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